Genetic Basis of Excessive Gingival Display in Eastern Mediterranean Families

Abstract

Background: Excessive gingival display – EGD (Gummy smile) is a condition in which a high lip-line exposes a large amount of gingival tissue upon smiling. Several potential factors could contribute to EGD: excessive vertical maxillary growth, short upper lip, hypermobile upper lip, altered passive eruption (short clinical crowns). EGD is commonly present within the long face syndrome (LFS) which is the second most inherited facial condition. Treatment of this condition may require an invasive surgical approach to correct bony positions and decrease or eliminate EGD. However, EGD may be separate from the LFS.

Aims: 1. Investigate the inheritance pattern of excessive gingival display in Eastern Mediterranean population; 2. Identify candidate loci and gene(s) responsible of the development and familial transmission of EGD in the studied Mediterranean population; 3. Evaluate the skeletal and dento-alveolar cephalometric characteristics of individuals affected by EGD.

Methods: Pedigrees of 4 Mediterranean families with individuals of different generations having EGD were included. 21 subjects (Affected and non-affected) underwent a detailed data and biospecimen collection procedure. This consisted of: (1) a clinical examination during which a set of extraoral photographs were captured; (2) lateral cephalometric radiograph to assess the skeletal and dentoalvelolar features of all participants and (3) 5cc of blood collection from affected and some non-affected members. The elevation of the upper lip, height of clinical crowns and the incisor display at rest were measured on photographs. The upper lip length, divergence pattern, vertical maxillary height, position of the jaws and the inclination of maxillary and mandibular teeth were measured on the lateral cephalometric radiographs. Next Generation Sequencing (NGS) technology was used and a Whole Exome Sequencing was applied to determine the genetic determinants of EGD.

Results: A Mendelian inheritance pattern was observed segregating in either an autosomal dominant or X-linked manner. Pedigree analysis showed a female predominance among affected individuals. Extraoral photographs demonstrated that EGD is transmitted with different levels of penetrance. A hypermobile upper lip was present in 5 affected individuals. Short clinical crowns were observed in 6 affected subjects. A normal or slightly increase upper lip length was measured among individuals having EGD. Cephalometric analysis on affected subjects revealed an increased lower facial height, a hyperdivergent facial pattern, an increased anterior vertical maxillary height, a tendency towards a skeletal class II and retroclined maxillary incisors. Genetic analysis denoted the presence of 33 novel genes affecting skeletal and muscular development. HERC2 gene could have a direct impact on the transmission of EGD.

Conclusion: This is the first study evaluating the inheritance pattern and genetic contribution to EGD. It illustrated the clinical, cephalometric characteristics of affected individuals and shed light on the genetic map responsible for the development of EGD. The presence of multiple etiologic factors responsible for EGD do not necessarily point to a skeletal discrepancy but also to a muscular alteration and to a lesser extent to dental contribution. Vertical maxillary excess is the main determinant of the condition.